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Strategies for Managing Autoimmune Complications in CLL


While chronic lymphocytic leukemia (CLL) typically progresses slowly, awareness of rare but potentially serious complications is crucial to improve outcomes.

Chronic lymphocytic leukemia (CLL) is a common and typically indolent malignancy, but some patients present with rapidly progressing disease that can transform into non-Hodgkin lymphoma (NHL). A review published in the American Journal of Hematology details autoimmune and extranodal complications that can arise and summarizes current management strategies.

While there is no known cure for CLL, which is characterized by leukemic involvement of bone marrow, blood, and lymphoid organs, the course of disease is most often slow and the median age at diagnosis is 71 years. As CLL progresses, increased bone marrow involvement and splenomegaly cause cytopenias, and enlarged lymph nodes may occur. Systemic symptoms can include fevers, night sweats, fatigue, and fat loss—but in general, patients with CLL do not undergo treatment until advanced symptoms are present, and some patients do not require therapy specifically for CLL.

Autoimmune complications are relatively common in patients with CLL due to various mechanisms, and there is a risk of serious infections as well as other cancers. Autoimmune-mediated complications outlined in the review include autoimmune cytopenias (AIC), autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), pure red cell aplasia (PRCA), and autoimmune granulocytopenia (AIG).

Routinely evaluating patients with CLL for AIHA is recommended, especially as CLL enters more advanced stages. Rapid onset of anemia, anemia with a relatively preserved platelet count, and laboratory reports showing high bilirubin, lactate dehydrogenase and reticulocyte counts are all indicative of potential AIHA. Directing antigen Coombs testing for the presence of auto-reactive antibodies targeting red blood cells can help identify autoantibodies characteristic of AIHA versus those typically present in cold agglutinin disease, a subtype of AIHA.

Regarding treatment for AIHA, the strategy depends on a patient’s CLL treatment regimen or lack thereof. In those who meet the International Working Group on CLL criteria for CLL-directed therapy, this is the preferred option to manage AIHA. For patients who are not eligible for CLL-directed therapy, immunosuppressive therapy is recommended. When patients do not respond to immunosuppression, CLL-directed therapy is an option to consider.

In patients with ITP, thrombocytopenia occurs due to platelet destruction and decreased production. When patients with CLL have isolated or quickly worsening thrombocytopenia, especially without splenomegaly or bone marrow failure, providers should consider ITP. CLL-directed therapy is the recommended frontline treatment for ITP in eligible patients, and steroids are the preferred treatment for patients who require treatment for ITP but are not eligible for CLL-directed therapy. Treatment of concurrent ITP and AIHA, known as Evans syndrome, is managed similarly.

PRCA is a rare complication that can be difficult to differentiate from AIHA. Indicators of PRCA include anemia, a low reticulocyte count, and a negative Coombs test to help rule out AIHA. In AIG, patients present with isolated or disproportionate neutropenia. Both PRCA and AIG need to be differentiated from chemotherapy-related myelodysplastic syndrome and acute myeloid leukemia in patients with CLL who have undergone chemotherapy previously. Treatments for PRCA and AIG are similar to the above AICs, with CLL-directed therapy or immunosuppression in patients who are not eligible for CLL-directed therapy.

In patients with CLL and unexplained bleeding, acquired von Willebrand disease or acquired hemophilia A may be considered, although these are both rare. Immunosuppression can be beneficial in both cases to manage these patients. Rare but serious non-hematologic AICs such as paraneoplastic pemphigus, glomerulonephritis, angioedema due to acquired complement 1 esterase inhibitor deficiency, and myasthenia gravis can also occur in patients with CLL.

Finally, the review also highlights extranodal involvement, which is rare in CLL and is generally only treated when symptomatic. The most common sites of extranodal involvement appear to be the skin, kidneys, and central nervous system, although the actual incidence of extranodal involvement in CLL is difficult to gauge.

Overall, the authors emphasize proper management of both common and rare autoimmune complications seen in patients with CLL. While this disease typically progresses slowly, awareness of rare but potentially serious complications is crucial to improve outcomes.


Gordon MJ, Ferrajoli A. Unusual complications in the management of chronic lymphocytic leukemia. Am J Hematol. Published online May 1, 2022. doi:10.1002/ajh.26585

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